Staphylococcus aureus
Staphylococcus aureus is a major human and animal pathogen against which a vaccine is urgently needed. The Gram-positive cocci frequently colonize human skin and mucosa asymptomatically, but factors that compromise the immune system or provide access to deeper tissues can lead to serious infections. Under the appropriate conditions, S. aureus can invade nearly every organ system, causing life-threatening infections such as wound abscess, kidney infection, endocarditis, osteomyelitis, meningitis, arthritis, pneumonia and septicemia, toxic shock syndrome and necrotizing pneumonia. Antimicrobial resistance has become commonplace among S. aureus strains that are highly prevalent in healthcare institutions. Most clinical isolates are resistant to multiple antimicrobials, including methicillin, and these have been dubbed 'MRSA,' meaning "methicillin-resistant Staphylococcus aureus." Disturbingly, the rapid emergence of community-acquired MRSA infections suggests that these multi-resistant pathogens are quickly disseminating throughout the broader community. Vancomycin is the typical antimicrobial of last resort for combating MRSA infections. Although still rare, vancomycin resistant S. aureus have been isolated in several countries, further underscoring the need for a protective vaccine.
Yersinia pestis
Yersinia pestis, a Gram-negative bacillus, is the causative agent of plague. Plague is undoubtedly one of the most devastating acute infectious diseases in recorded human history, estimated to have killed 100 to 200 million people worldwide. Plague is an epizoonotic disease, spreading from rodents to fleas, which serve as natural vectors for transmission to humans. Thus, under natural circumstances, Y. pestis typically infects humans by a subcutaneous route into the bloodstream, travels to the lymph nodes and begins multiplying. Clinical manifestations of plague include large swollen masses near the lymph nodes, referred to as bubos. Occasionally, Y. pestis multiplies rapidly in the bloodstream, inducing septicemia with an accompanying general malaise that includes fever, headache, chills, and gastrointestinal disturbances. These symptoms are often misdiagnosed, and antibiotic therapy is therefore administered too late for effective intervention. Y. pestis septicemia has a 50% fatality rate, and can lead to pulmonary infection. The pneumonic form of plague is extremely infectious by the respiratory droplet route and is characterized by a rapid onset of disease and a mortality rate close to 100%. Although natural infection by Y. pestis is rare in this country, there is fear that the organism will become an agent of bioterrorism. There are currently no vaccines to protect against such a threat.
Salmonella enterica
The Gram-negative bacterium Salmonella enterica is a major human and animal pathogen that causes infection following ingestion of contaminated food or water. There are over 2000 recognized serovars of S. enterica that cause millions of infections annually throughout the world. These serovars can be divided loosely into two categories: the serovars Typhi and Paratyphi that cause typhoid fever in humans, and the non-typhoidal serotypes such as Typhimurium and Newport that generally cause gastroenteritis in humans and other animals. In developed
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countries, the non-typhoid serovars are typically more commonthan the typhoid-causing serovars. Gastroenteritis due to Salmonella is usually self-limiting and resolves itself within a week. While deaths due to this disease are relatively rare in the United States, antibiotic resistance is increasingly problematic. Typhoid fever is a serious systemic illness that affects tens of millions of people worldwide and causes hundreds of thousands of deaths. Two typhoid vaccines are currently available, but their efficacy rates are 30-80%, and often are not recommended for infants.
Bacillus anthracis
Bacillus anthracis, the causative agent of anthrax, is a Gram-positive, spore-forming bacterium that naturally resides in the soil. It typically causes a fatal septicemia in herbivores that come into contact with dormant bacterial spores. Infection of humans is rare, and usually restricted to people who work with animals or animal products. Cutaneous anthrax is the most common form of human disease and develops from the infection of an open wound to an ulcerative skin lesion. Intestinal anthrax can result from ingestion of contaminated meat, primarily beef cattle. Most serious is inhalation anthrax, which results in a severe respiratory infection and mortality rates approaching 100% within 2-3 days after exposure. The principle bacterial virulence factor is a multi-component toxin system that is responsible for the edema and lethality associated with the disease. If recognized early, anthrax can be treated with antibiotics, such as penicillin or ciprofloxacin. Due to the bioterrorism attacks in the United States, attention given to anthrax disease and its potential use as a bioweapon increased dramatically. A human vaccine for anthrax exists, but is recommended only for military personnel or those who are at direct risk of anthrax exposure. In addition, the safety and efficacy of the current vaccine is somewhat controversial.
Burkholderia pseudomallei
Burkholderia pseudomallei is a Gram negative bacterium found in soil, and on contaminated food and water. It is the causative agent of melioidosis and of public health importance in endemic areas, particularly in Thailand and northern Australia. Transmission to humans and animals occurs through direct contact with the organism in the environment via ingestion, inhalation, or through open wounds and skin abrasions. Manifestation of melioidosis can be categorized as acute localized skin infection, septicemia, acute pulmonary infection, or chronic infection. Chronic infections often develop with secondary abscesses in the skin, brain, lungs, liver, spleen, bones, lymph nodes, or eyes. Without access to appropriate antibiotics (principally ceftazidime or meropenem), the septicemic form of melioidosis has a mortality rate that exceeds 90%. With appropriate antibiotics, the mortality rate is about 10% for uncomplicated cases but up to 80% for cases with bacteremia or severe sepsis. The severe course of infection, aerosol infectivity and worldwide availability of this pathogen has resulted in its inclusion as a potential agent of biological warfare or bioterrorism, and is listed on the Centers for Disease Control list as a Category B bioterrorism agent. There is no vaccine at this time and the organism is often refractory to antibiotic therapy especially after it has established itself.
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